Dendroid peptide structural mimetics of ω-conotoxin MVIIA based on a 2(1H)-quinolinone core

Article abstract of DOI:10.1016/S0040-4020(00)00179-4

Three mimetics of the peptide ω-Conotoxin MVIIA have been synthesised following the dendroid approach. The three key central amino acids of the natural peptide are mimicked by phenylguanidine (arginine), isopentyl (leucine) and aryl alcohol (tyrosine) att

Full text of DOI:10.1016/S0040-4020(00)00179-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5169±5175
Dendroid Peptide Structural Mimetics of v-Conotoxin MVIIA
based on a 2(1H)-Quinolinone Core
b
Zhao-Xia Guo,a Andrew N. Cammidgea, and David C. Horwell
*
aSchool of Chemical Sciences, University of East Anglia, Norwich NR4 7TJ, UK
bParke±Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge CB2 2QB, UK
Received 23 November 1999; revised 8 February 2000; accepted 24 February 2000
AbstractÐThree mimetics of the peptide v-Conotoxin MVIIA have been synthesised following the dendroid approach. The three key
central amino acids of the natural peptide are mimicked by phenylguanidine (arginine), isopentyl (leucine) and aryl alcohol (tyrosine)
attached to a quinolinone core at the 1- and 8-positions. The derivatives are designed to position these key groups in similar spatial orientation
to that of the natural peptide in a structure that will have limited conformational ¯exibility. Key steps of the syntheses involve selective
N-alkylation of quinolinone derivatives and guanylation of aryl amines. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
v-Conotoxin MVIIA, which is isolated from the venom of
the cone shell conus magnus,1 is a 25 amino-acid residue
containing peptide with three disul®de bonds. It is a
promising new drug for the treatment of severe neuropathic
pain2 whose analgesic effect is derived from a highly selec-
tive modulation of N-type neuronal calcium ion channels.3
The synthetic equivalent SNX-III (ziconotide) has demon-
strated therapeutic bene®t in animal models of traumatic
brain injury, focal cerebral ischemia and pain.4 However,
total synthesis of SNX-III is time consuming and expensive,
and the drug cannot be administered orally. Recent progress
in the area of small molecule N-type calcium channel block-
ers has been reviewed.5
Our strategy for the synthesis of conotoxin mimetics follows
the `dendroid' approach.6,7 This strategy involves placement
of mimetics of the key residues around a central core. The
overall structure has intermediate conformational freedom
and allows the key groups to adopt similar spatial orien-
tations to that found in the natural product (based on the
3D structure of v-conotoxin MVIIA8).
The three key central amino acids important for SNX-III
binding to ion channels are leucine, tyrosine and arginine.
Based on this information, and the 3D structure, we chose
dendroids I±III as synthetic targets.
Keywords: quinolinones; peptide mimetics; guanidines; calcium ion chan-
nels.
* Corresponding author. E-mail: a.cammidge@uea.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00179-4

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Z.-X. Guo et al. / Tetrahedron 56 (2000) 5169±5175
Scheme 1. Synthesis of dendroid I: (i) BOC2O, THF, re¯ux, 4 h; (ii) CBr4, PPh3, CH2Cl2, 08C, 1 h; (iii) K2CO3, acetone, re¯ux, 5 h; (iv) i-pentyl bromide,
K2CO3, 18-crown-6, acetone, re¯ux, 5 h; (v) K2CO3, acetone, re¯ux, 15 h; (vi) KOH, TBAI, toluene, 508C, 4 h; (vii) TFA, CH2Cl2, rt, 2 h; (viii) HgCl2, Et3N,
DMF, 08C, 3 h then rt, 2 h; (ix) K2CO3, MeOH, rt, 1 h; (x) TFA, CH2Cl2, rt, 5 h.
8-Hydroxy-2-(1H)-quinolinone was chosen as core because
we anticipate that steric crowding will impede confor-
mational freedom and give non-planar structures. Further-
more, we expected it to be straightforward to perform
sequential alkylations on the 8-hydroxyl and nitrogen. In
all cases arginine was mimicked by phenyl guanidine and
leucine by isopentyl. In dendroids I and II tyrosine was
mimicked by phenols, whereas in III it is mimicked by
the 2-hydroxyquinoline tautomer.
isopentyl bromide also employed potassium carbonate in
re¯uxing acetone but required addition of 18-C-6 catalyst
to achieve a reasonable reaction rate. Bromination of benzyl
alcohol 5 was best achieved using CBr4/PPh3 in dichloro-
methane to give benzyl bromide 6. 8-Hydroxy-2-(1H)-
quinolinone was then alkylated (on the 8-hydroxyl) with 6
by treatment with potassium carbonate in re¯uxing acetone
to give intermediate 7 in 85% yield.
3-Hydroxybenzyl alcohol was selectively acetylated on the
phenolic hydroxyl (ice cold acetic anhydride/KOH10) before
conversion of the benzyl alcohol to the corresponding bro-
mide (by treatment with PBr3) to give 8 in an overall yield of
44%. Selective N-alkylation of 7 with 3-acetoxybenzyl bro-
mide 8 was achieved using similar conditions to the most
selective found in our model studies11 (toluene/KOH/TBAI)
to give 9 in 38% yield. The N- vs. O-selectivity ratio was
determined to be 2.3:1 (by analysis of the 1H NMR spectrum
of the crude mixture), similar to that observed in the model
studies. The low yield was due to slow reaction of the bro-
mide 8, leading to incomplete reaction (30% of the starting
material was recovered). The BOC protecting group on 9
Results and Discussion
Synthesis of dendroid I
The synthesis of dendroid I is outlined in Scheme 1. 3-
Aminobenzyl alcohol was BOC-protected and brominated
following literature procedures9 to give benzyl bromide 3.
Compound 3 was treated with 4 equiv. of 3,5-dihydroxy-
benzyl alcohol and potassium carbonate in re¯uxing acetone
to give the monoalkylated product 4 in 41% yield. Alkyl-
ation of the second phenolic hydroxyl group of 4 with

Z.-X. Guo et al. / Tetrahedron 56 (2000) 5169±5175
5171
Scheme 2. Syntheses of dendroids II and III: (i) KOH(aq), Ac2O, 08C, 45 min; (ii) PBr3, toluene, 08C, 1.5 h; (iii) CBr4, PPh3, CH2Cl2, 08C, 1 h; (iv) KOH,
TBAI, toluene, 508C, 4 h; (v) TFA, CH2Cl2, rt, 2 h; (vi) HgCl2, Et3N, DMF, 08C, 3 h then rt, 2 h; (vii) K2CO3, MeOH, rt, 1 h; (viii) TFA, CH2Cl2, rt, 5 h.
was removed by treatment with TFA in dichloromethane at
room temperature to give the free aniline 10 in 90% yield.
Guanylation of 10 with 1,3-bis-BOC-2-methyl-2-thio-
pseudourea 11 in the presence of mercury chloride gave
following similar N-alkylation (in the case of dendroid II),
deprotection and guanylation procedures to those employed
for the synthesis of dendroid I, as shown in Scheme 2.
1
bis-BOC protected guanidine 12 in 86% yield. The H and
13C NMR spectra imply that 12 exists essentially as a single
tautomer.
Conclusions
Three mimetics of the peptide v-Conotoxin MVIIA have
been synthesised in which a quinolinone core is elaborated
at the 1- and 8-positions to generate a dendroid structure
which incorporates a phenylguanidine (arginine), isopentyl
(leucine) and an aryl alcohol (tyrosine).
The acetate protecting group on 12 was removed under mild
conditions by stirring with potassium carbonate in methanol
at room temperature (75%). Finally the BOC protecting
groups on guanidine 13 were removed by treatment with
TFA in dichloromethane to give dendroid I as its TFA salt
(76%). Attempts to prepare the HCl salt of dendroid I using
a literature procedure12 (treatment of 13 with tin chloride in
ethyl acetate) were unsuccessful. Treatment of 13 with 1 M
HCl in ether13 caused partial reaction to afford a mixture of
starting material and products from removal of one and both
BOC protecting groups. Further reaction, however, was
prevented by precipitation.
Experimental
Column chromatography was carried out with Merck
Kieselgel 60 (70±230 mesh). NMR spectra were measured
on a Varian Gemini 2000 instrument using TMS as internal
standard. IR spectra were recorded on a Perkin±Elmer FTIR
1720 instrument. Routine mass spectra (EI) were performed
on a Kratos MS 25 mass spectrometer. Melting points are
uncorrected.
Synthesis of dendroids II and III
Dendroids II and III were synthesised from intermediate 7

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Z.-X. Guo et al. / Tetrahedron 56 (2000) 5169±5175
3-(30-N-BOC-Aminobenzyloxy)-5-hydroxybenzyl alcohol
4. A mixture of 3,5-dihydroxybenzyl alcohol (25.78 g,
4 equiv.), 3-N-BOC-aminobenzyl bromide (13.16 g,
46 mmol) and potassium carbonate (12.71 g, 2 equiv.)
were stirred in re¯uxing acetone (300 ml) for 5 h under
nitrogen. After cooling to room temperature the mixture
was concentrated in vacuo and the residue treated with
water (400 ml) and extracted with dichloromethane
(600 ml then 2£100 ml). The combined organic extracts
were dried (Na2SO4) and the solvent evaporated to give
the crude product as an amorphous solid which was puri®ed
by column chromatography (silica, CH2Cl2/methanol
0±2%) to give a white solid which was recrystallised from
acetone/light petroleum (6.51 g, 41%). Mp 149.3±150.88C;
CHN Calcd for C19H23NO5: C, 66.07; H, 6.71; N, 4.06.
Found: C, 66.16; H, 6.69; N, 3.96; IR (nujol) nmax 3300,
ethyl acetate/petroleum ether 1:30 to 1:15) to give 6 as
white needles (4.77 g, 87%). Mp 78.7±79.98C; CHN
Calcd for C24H32NO4Br: C, 60.25; H, 6.74; N, 2.93; Br,
16.70. Found: C, 60.53; H, 6.74; N, 2.79; Br, 16.41; IR
(nujol) nmax 3260, 1680, 1595, 1535 cm21 1H NMR
;
(300 MHz, CDCl3) dH, 0.95 (6H, d, Jˆ6.6 Hz), 1.52 (9H,
s), 1.65 (2H, q, Jˆ6.6 Hz), 1.73±1.86 (1H, m), 3.95 (2H, t,
Jˆ6.6 Hz), 4.40 (2H, s), 4.99 (2H, s), 6.45 (1H, t,
Jˆ2.1 Hz), 6.54±6.55 (1H, m), 6.57±6.58 (2H, m), 7.07±
7.10 (1H, m), 7.28±7.32 (2H, m), 7.46 (1H, brs); 13C NMR
(75 MHz, CDCl3) dC, 22.63, 25.09, 28.39, 33.73, 37.98,
66.66, 70.05, 80.76, 101.98, 107.83, 108.19, 117.60,
118.28, 122.18, 129.48, 137.98, 138.94, 139.89, 152.98,
160.25, 160.71; LRMS (EI): 479 (M1, 2%), 477 (M1,
2%), 342 (2%), 298 (3%), 106 (18%), 82 (41%), 80
(41%), 41 (100%).
1
1697, 1600, 1537 cm21; H NMR (300 MHz, Acetone-d6)
dH, 1.48 (9H, s), 4.21 (1H, brs), 4.54 (2H, s), 5.02 (2H, s),
6.36±6.38 (1H, m), 6.48±6.49 (1H, m), 6.54±6.55 (1H, m),
7.07±7.09 (1H, m), 7.28 (1H, t, Jˆ8 Hz), 7.50 (1H, d,
Jˆ8 Hz), 7.68 (1H, s), 8.29 (1H, brs), 8.44 (1H, brs); 13C
NMR (75 MHz, acetone-d6) dC, 28.55, 64.73, 70.41, 80.13,
101.67, 105.15, 107.15, 118.19, 118.57, 122.27, 129.76,
139.39, 140.93, 146.04, 153.98, 159.49, 161.21; LRMS
(EI): 245 (2%), 106 (9%), 41 (100%).
8-[30-(i-Pentyloxy)-50-(300-N-BOC-aminobenzyloxy)benzyl-
oxy]-2-[1H]-quinolinone 7. A mixture of 3-(30-N-BOC-
aminobenzyloxy)-5-i-pentyloxybenzyl bromide 6 (9.09 g,
19 mmol), 8-hydroxy-2(1H)-quinolinone (3.06 g, 19
mmol) and potassium carbonate (5.25 g, 2 equiv.) were
stirred overnight in re¯uxing acetone (200 ml). After cool-
ing to room temperature the mixture was concentrated in
vacuo and the residue treated with water (300 ml) and
extracted with dichloromethane (600 ml then 100 ml). The
combined organic extracts were washed with brine, dried
(Na2SO4) and the solvent evaporated to give the crude
product as a brown oil which was puri®ed by column
chromatography (silica, ethyl acetate/petroleum ether 1:4
to 1:1.5) to give 7 as a white solid (8.97 g, 85%). Mp
152.7±153.98C; CHN Calcd for C33H38N2O6: C, 70.95; H,
6.86; N, 5.01. Found: C, 70.92; H, 6.84; N, 5.01; IR (nujol)
3-(30-N-BOC-Aminobenzyloxy)-5-i-pentyloxybenzyl alco-
hol 5. A mixture of 3-(30-N-BOC-aminobenzyloxy)-5-
hydroxybenzyl alcohol 4 (9.84 g, 28.5 mmol), i-pentyl bro-
mide (10.70 ml, 3 equiv.), potassium carbonate (7.87 g,
2 equiv.) and 18-crown-6 (1.51 g, 0.2 equiv.) was stirred
in re¯uxing acetone (220 ml) for 5 h under nitrogen. After
cooling to room temperature the mixture was concentrated
in vacuo and the residue treated with water (100 ml) and
extracted with ethyl acetate (150 ml then 2£60 ml). The
combined organic extracts were washed with brine, dried
(Na2SO4) and the solvent evaporated to give the crude
product as an amorphous off-white solid which was puri®ed
by column chromatography (silica, ethyl acetate/petroleum
ether 1:10 to 1:3) to give 5 as white solid (10.90 g, 92%). Mp
96.9±97.78C; CHN Calcd for C24H33NO5: C, 69.37; H, 8.00;
N, 3.37. Found: C, 69.51; H, 8.05; N, 3.27; IR (nujol) nmax
1
nmax 3400, 3220, 1712, 1655, 1605, 1545 cm21; H NMR
(300 MHz, CDCl3) dH, 0.95 (6H, d, Jˆ6.6 Hz), 1.50 (9H, s),
1.65 (2H, q, Jˆ6.6 Hz), 1.71±1.87 (1H, m), 3.95 (2H, t,
Jˆ6.6 Hz), 5.01 (2H, s), 5.09 (2H, s), 6.51 (1H, t, Jˆ
2.2 Hz), 6.55±6.56 (1H, m), 6.59±6.60 (1H, m), 6.67 (1H,
d, Jˆ9.7 Hz), 6.95 (1H, s), 6.98 (1H, dd, Jˆ7.8, 1.4 Hz),
7.05±7.10 (2H, m), 7.14 (1H, dd, Jˆ7.8, 1.4 Hz), 7.24±7.29
(1H, m), 7.33±7.36 (1H, m), 7.47 (1H, s), 7.72 (1H, d,
Jˆ9.7 Hz), 9.30 (1H, brs); 13C NMR (75 MHz, CDCl3)
dC, 22.62, 25.05, 28.38, 37.96, 66.66, 70.10, 71.11, 80.56,
101.74, 106.36, 106.86, 111.82, 117.55, 118.28, 120.07,
120.34, 121.99, 122.43, 122.77, 128.89, 129.45, 137.96,
138.11, 139.11, 140.69, 144.74, 153.11, 160.48, 160.93,
162.32; LRMS (EI): 458 (9%), 298 (22%), 161 (60%),
106 (100%).
1
3410, 3230, 1695, 1595, 1550 cm21; H NMR (300 MHz,
CDCl3) dH, 0.94 (6H, d, Jˆ6.8 Hz), 1.51 (9H, s), 1.64 (2H,
q, Jˆ6.8 Hz), 1.76±1.83 (1H, m), 2.14 (1H, t, Jˆ6.0 Hz),
3.94 (2H, t, Jˆ6.8 Hz), 4.58 (2H, d, Jˆ6.0 Hz), 4.98 (2H, s),
6.43 (1H, t, Jˆ2.4 Hz), 6.51±6.52 (1H, m), 6.55±6.56 (1H,
m), 6.66 (1H, brs), 7.05±7.09 (1H, m), 7.26±7.29 (2H, m),
7.44 (1H, brs); 13C NMR (75 MHz, CDCl3) dC, 22.39, 24.86,
28.15, 37.77, 65.10, 66.36, 69.69, 80.53, 100.89, 105.19,
105.55, 117.51, 118.05, 121.97, 129.19, 137.94, 138.64,
143.42, 152.86, 160.05, 160.52; LRMS (EI): 415 (M1,
4%), 359 (2%), 315 (14%), 106 (100%).
3-Acetoxybenzyl alcohol. To a stirred solution of 3-hydro-
xybenzyl alcohol (3.72 g, 30 mmol) in 6.4N aqueous KOH
(7 ml) at room temperature was added ice (15 g) followed
by acetic anhydride (3.55 ml, 1.25 equiv.). After stirring for
45 min, water (250 ml) was added and the mixture was
stirred for a further 30 min before extracting with dichloro-
methane (3£100 ml). The combined extracts were washed
with water, brine and dried (Na2SO4). Evaporation of the
solvent gave a brown oil which was puri®ed by column
chromatography (silica, ethyl acetate/petroleum ether 1:6
to 1:4) to give 3-acetoxybenzyl alcohol14 as a colourless
oil (3.24 g, 65%).
3-(30-N-BOC-Aminobenzyloxy)-5-i-pentyloxybenzyl bro-
mide 6. Carbon tetrabromide (5.72 g, 1.5 equiv.) was
added portionwise over 20 min to a stirred solution of
3-(30-N-BOC-aminobenzyloxy)-5-i-pentyloxybenzyl alco-
hol 5 (4.78 g, 11.5 mmol) and triphenyl phosphine (4.52 g,
1.5 equiv.) in dry dichloromethane (80 ml) at 08C under
nitrogen. The resulting pale yellow solution was stirred at
08C for a further 1 h and then concentrated in vacuo. The
residue was puri®ed by column chromatography (silica,
3-Acetoxybenzyl bromide 8.15 PBr3 (1.53 ml, 0.5 equiv.)

Z.-X. Guo et al. / Tetrahedron 56 (2000) 5169±5175
5173
was added dropwise to a solution of 3-acetoxybenzyl alco-
hol (5.4 g, 32.5 mmol) in dry toluene (75 ml) at 08C under
nitrogen. The mixture was stirred for a further 1.5 h then
diluted with ethyl acetate (150 ml), washed with brine and
dried (Na2SO4). Evaporation of the solvents gave a crude oil
which was puri®ed by column chromatography (silica, ethyl
acetate/petroleum ether 1:30) to give 8 as a colourless oil
(5.07 g, 68%).
22.63, 25.09, 38.01, 49.34, 66.57, 70.17, 72.12, 101.58,
105.92, 106.39, 114.03, 114.89, 115.48, 117.54, 119.29,
119.47, 122.02, 122.30, 123.22, 123.43, 123.45, 129.22,
129.73, 130.76, 138.25, 138.66, 140.26, 141.32, 147.11,
147.52, 150.96, 160.48, 160.78, 163.81, 169.54; LRMS
(EI), 606 (1%, M1), 530 (12%), 106 (100%); HRMS (ES),
Calcd for C37H39N2O6 (M11H): 607.2808; Found: M11H:
607.2819.
8-[30-(i-Pentyloxy)-50-(300-N-BOC-aminobenzyloxy)benzyl-
oxy]-2-[1-(3000-acetoxybenzyl)]-quinolinone 9. To a stirred
suspension of 8-[30-(3-i-pentyloxy)-50-(300-N-BOC-amino-
Bis-BOC-guanidine 12. To a stirred solution of 10 (2.06 g,
3.40 mmol) and 1,3-bis-BOC-2-methyl-2-thiopseudourea
11 (1.04 g, 1.05 equiv.) in dry DMF (50 ml) at 08C under
nitrogen was added triethylamine (1.89 ml, 4 equiv.) and
HgCl2 (1.01 g, 1.1 equiv.). The resulting white suspension
was stirred at 08C for 3 h and then at room temperature for
2 h. The mixture was diluted with ethyl acetate (300 ml) and
®ltered through Celite. The ®ltrate was washed with water
(400 ml) and the aqueous layer was extracted with ethyl
acetate (2£80 ml). The combined organic extracts were
®ltered through Celite, washed with brine and dried
(Na2SO4). Evaporation of the solvent gave the crude product
as a gum which was puri®ed by column chromatography
(silica, ethyl acetate/petroleum ether 1:4 to 1:2) to give 12 as
a white foam (2.49 g, 86%). CHN Calcd for C48H56N4O10´
0.25 EtOAc: C, 67.57; H, 6.71; N, 6.43. Found: C, 67.22; H,
benzyloxy) benzyloxy]-2(1H)-quinolinone
7
(6.00 g,
10.74 mmol) and 3-acetoxybenzyl bromide (3.44 g,
1.4 equiv.) in dry toluene (80 ml) at room temperature
under nitrogen was added TBAI (793 mg, 0.2 equiv.) and
powdered KOH (844 mg, 1.4 equiv.). The mixture was
heated at 508C for 4 h. After cooling to room temperature
the mixture was stirred over Na2SO4 for 10 min and then
®ltered through Celite. The ®ltrate was concentrated in
vacuo to give a yellow oil which was puri®ed by column
chromatography (silica, ethyl acetate/petroleum ether 1:4 to
1:2.5) to give 9 as a white foam (2.90 g, 38%). CHN Calcd
for C42H46N2O8. 0.27 EtOAc: C, 70.82; H, 6.64; N, 3.83.
Found: C, 70.72; H, 6.68; N, 3.69; IR (nujol) nmax 3240,
1760, 1717, 1650, 1585 cm21; 1H NMR (300 MHz, CDCl3)
dH, 0.95 (6H, d, Jˆ6.6 Hz), 1.50 (9H, s), 1.65 (2H, q,
Jˆ6.6 Hz), 1.77±1.86 (1H, m), 2.19 (3H, s), 3.90 (2H, t,
Jˆ6.6 Hz), 4.79 (2H, s), 4.93 (2H, s), 5.88 (2H, s), 6.35±
6.37 (2H, m), 6.46 (1H, t, Jˆ2.2 Hz), 6.69±6.87 (5H, m),
6.96±7.24 (5H, m), 7.26±7.30 (2H, m), 7.49 (1H, s), 7.67
(1H, d, Jˆ9.5 Hz); 13C NMR (75 MHz, CDCl3) dC, 21.14,
22.63, 25.09, 28.39, 38.01, 49.40, 66.59, 69.97, 72.11,
80.65, 101.52, 105.86, 106.48, 115.51, 117.54, 118.24,
119.29, 119.51, 122.03, 122.31, 123.25, 123.44, 123.50,
129.25, 129.42, 130.76, 138.05, 138.70, 139.04, 140.27,
141.31, 147.52, 150.97, 153.01, 160.35, 160.78, 163.84,
169.59; HRMS (ES), Calcd for C42H47N2O8 (M11H):
707.3332; Found: M11H: 707.3347.
6.69; N, 6.31; IR (®lm) nmax 1766, 1719, 1641, 1596 cm21
;
1H NMR (300 MHz, CDCl3) dH, 0.96 (6H, d, Jˆ6.6 Hz),
1.50 (9H, s),1.54 (9H, s), 1.65 (2H, q, Jˆ6.6 Hz), 1.78±1.87
(1H, m), 2.18 (3H, s), 3.91 (2H, t, Jˆ6.6 Hz), 4.80 (2H, s),
4.94 (2H, s), 5.90 (2H, s), 6.36 (2H, d, Jˆ2.2 Hz), 6.48 (1H,
t, Jˆ2.2 Hz), 6.71±6.72 (1H, m), 6.77 (1H, d, Jˆ9.4 Hz),
6.81±6.83 (1H, m), 6.85±6.88 (1H, m), 6.98 (1H, dd, Jˆ8.0,
1.6 Hz), 7.07 (1H, t, Jˆ7.8 Hz), 7.14±7.19 (3H, m), 7.33
(1H, t, Jˆ7.8 Hz), 7.59 (1H, m), 7.64±7.68 (1H, m), 7.67
(1H, d, Jˆ9.4 Hz), 10.37 (1H, s), 11.67 (1H, s); 13C NMR
(75 MHz, CDCl3) dC, 21.13, 22.63, 25.08, 28.14, 28.23,
38.01, 49.43, 66.58, 69.84, 72.15, 79.82, 83.94, 101.61,
105.83, 106.44, 115.55, 119.28, 119.53, 121.12, 122.03,
122.12, 122.32, 123.22, 123.41, 123.48, 123.86, 129.26,
129.39, 130.80, 137.35, 137.93, 138.73, 140.24, 141.34,
147.52, 151.01, 153.60, 153.81, 160.34, 160.80, 163.78,
169.49; HRMS (ES), Calcd for C48H57N4O10 (M11H):
849.4075; Found: M11H: 849.4063.
8-[30-(3-i-Pentyloxy)-50-(300-aminobenzyloxy)benzyloxy]-
2-[1-(3000-acetoxybenzyl)]-quinolinone 10. To a stirred
solution of 9 (2.84 g, 4.02 mmol) in dichloromethane
(70 ml) was added, over 5 min, tri¯uoroacetic acid
(12.06 ml, 39 equiv.). The mixture was stirred at room
temperature for 2 h then concentrated in vacuo. The residue
was treated with saturated aqueous NaHCO3 (80 ml) and
extracted with ethyl acetate (110 ml the 2£40 ml). The
combined organic extracts were washed with brine, dried
(Na2SO4) and the solvent evaporated to give a pale yellow
foam (2.41 g) which was puri®ed by column chromato-
graphy (silica, ethyl acetate/petroleum ether 1:4 to 1:0.8)
to give 10 as a white foam (2.20 g, 90%). CHN Calcd for
C37H38N2O6. 0.12 EtOAc: C, 72.93; H, 6.36; N, 4.54.
Found: C, 72.76; H, 6.35; N, 4.48; IR (®lm) nmax 1757,
Deacetylation of bis-BOC-guanidine 12 to give 13. Potas-
sium carbonate (435 mg, 1.15 equiv.) was added to a solu-
tion of 12 (2.31 g, 2.72 mmol) in methanol (70 ml) at room
temperature under nitrogen and stirred for a further 1 h. The
mixture was concentrated in vacuo and the residue treated
with water and extracted with ethyl acetate (110 ml and
2£30 ml). The combined organic layers were washed with
brine and dried (Na2SO4). Evaporation of the solvents gave
a white foam (2.25 g) which was puri®ed by column
chromatography (silica, ethyl acetate/petroleum ether 1:3
to 1:2.5) to give 13 as white solid (1.66 g, 75%). mp
152.7±153.98C; CHN Calcd for C46H54N4O9: C, 68.47; H,
6.75; N, 6.94. Found: C, 68.54; H, 6.81; N, 6.77; IR (nujol)
1
1650, 1590 cm21; H NMR (300 MHz, CDCl3) dH, 0.95
(6H, d, Jˆ6.6 Hz), 1.65 (2H, q, Jˆ6.6 Hz), 1.75±1.89
(1H, m), 2.18 (3H, s), 3.71 (2H, br s), 3.90 (2H, t,
Jˆ6.6 Hz), 4.78 (2H, s), 4.89 (2H, s), 5.88 (2H, s), 6.35
(1H, m), 6.39 (1H, m), 6.47 (1H, t, Jˆ2.2 Hz), 6.59±6.63
(1H, m), 6.68 (1H, m), 6.72±6.80 (4H, m), 6.84±6.87 (1H,
m), 6.98 (1H, dd, Jˆ8.0, 1.5 Hz), 7.05±7.16 (4H, m), 7.67
(1H, d, Jˆ9.5 Hz); 13C NMR (75 MHz, CDCl3) dC, 21.12,
1
nmax 3253, 1728, 1646, 1630, 1611, 1598, 1582 cm21; H
NMR (300 MHz, CDCl3) dH, 0.95 (6H, d, Jˆ6.6 Hz), 1.45
(9H, s), 1.54 (9H, s), 1.65 (2H, q, Jˆ6.6 Hz), 1.75±1.86
(1H, m), 3.91 (2H, t, Jˆ6.6 Hz), 4.79 (2H, s), 4.87 (2H,
s), 5.87 (2H, s), 6.21 (1H, s), 6.37 (1H, m), 6.44±6.65
(5H, m), 6.94±7.15 (5H, m), 7.28 (1H, t, Jˆ7.8 Hz), 7.45

5174
Z.-X. Guo et al. / Tetrahedron 56 (2000) 5169±5175
(2H, t, Jˆ9.3 Hz), 7.59 (1H, s), 10.34 (1H, s), 11.70 (1H, br s);
13C NMR (75 MHz, CDCl3) dC, 22.63, 25.08, 28.16, 38.00,
49.65, 66.64, 69.67, 71.88, 80.34, 84.06, 101.77, 105.08,
106.60, 113.27, 113.92, 115.41, 117.66, 121.59, 121.96,
122.29, 122.37, 123.14, 123.44, 124.29, 129.32, 129.43,
130.74, 136.87, 138.09, 138.71, 140.27, 140.96, 147.53,
153.61, 154.22, 157.07, 160.43, 160.68, 163.62, 163.96.
Jˆ9.5 Hz); 13C NMR (75 MHz, CDCl3) dC, 21.16, 22.59,
25.07, 28.39, 35.50, 37.90, 48.39, 66.70, 70.16, 72.40,
80.48, 102.05, 106.64, 107.53, 114.84, 117.62, 118.29,
121.40, 121.99, 122.20, 122.47, 122.86, 123.41, 129.40,
130.03, 130.74, 137.16, 137.72, 138.16, 139.19, 139.77,
147.43, 149.16, 153.07, 160.71, 161.06, 163.72, 170.02;
HRMS (CI), Calcd for C43H48N2O8 (M11H): 721.348;
Found: M11H: 721.3481.
Dendroid I. A solution of 13 (200 mg) in dichloromethane
(4.1 ml) was treated with tri¯uoroacetic acid (0.70 ml,
37 equiv.) at room temperature and the resulting pale yellow
solution was stirred for a further 5 h. The solution was
concentrated in vacuo and the residue puri®ed by column
chromatography (silica, dichloromethane/methanol 4±10%)
to give dendroid I (142 mg, 76%). Rf 0.08 (CH2Cl2/MeOH
9:1). CHN Calcd for C36H38N4O5. 1.1 TFA. H2O: C, 61.16;
H, 5.52; N, 7.47; F, 8.36. Found: C, 60.99; H, 5.20; N, 7.26;
8-[30-(3-i-Pentyloxy)-50-(300-aminobenzyloxy)benzyloxy]-
2-[1-(4000-acetoxyphenyl)ethyl]-quinolinone 18. Synthe-
sised following a similar procedure to that for 10 to give
18 as a pale yellow foam (84%). IR (®lm) nmax 3456, 3356,
1
1757, 1654, 1594 cm21; H NMR (300 MHz, CDCl3) dH,
0.92 (6H, d, Jˆ6.6 Hz), 1.62 (2H, q, Jˆ6.6 Hz), 1.72±1.83
(1H, m), 2.25 (3H, s), 2.95±3.00 (2H, m), 3.60 (2H, brs),
3.90 (2H, t, Jˆ6.6 Hz), 4.70±4.75 (2H, m), 4.89 (2H, s),
5.07 (2H, s), 6.54±6.73 (7H, m), 6.83±6.95 (4H, m), 7.06±
7.16 (4H, m), 7.59 (1H, d, Jˆ9.3 Hz); 13C NMR (75 MHz,
CDCl3) dC, 21.14, 22.57, 25.04, 35.47, 37.88, 48.33, 66.64,
70.27, 72.34, 101.96, 106.79, 107.27, 114.02, 114.80,
114.88, 117.42, 121.40, 122.15, 122.43, 122.82, 123.37,
129.67, 130.02, 130.71, 137.14, 138.01, 138.13, 139.75,
147.19, 147.39, 149.17, 160.77, 161.04, 163.66, 169.84;
HRMS (CI), Calcd for C38H40N2O6 (M11H): 621.2964;
Found: M11H: 621.2960.
1
F, 8.56; IR (®lm) nmax 3362, 1683, 1650 1594 cm21; H
NMR (300 MHz, d6-acetone) dH, 0.95 (6H, d, Jˆ6.6 Hz),
1.63 (2H, q, Jˆ6.6 Hz), 1.76±1.87 (1H, m), 3.08 (4H, br s),
3.96 (2H, t, Jˆ6.6 Hz), 5.02 (2H, s), 5.03 (2H, s), 5.88 (2H,
s), 6.48±6.53 (5H, m), 6.60±6.64 (1H, m), 6.66 (1H, d,
Jˆ9.5 Hz), 7.00 (1H, t, Jˆ8.0 Hz), 7.10±7.20 (2H, m),
7.27±7.30 (2H, m), 7.39±7.47 (3H, m), 7.84 (1H, d,
Jˆ9.5 Hz), 7.94 (br s), 11.09 (1H, s); 13C NMR (75 MHz,
d6-acetone) dC, 22.86, 25.75, 38.69, 49.40, 67.06, 69.76,
72.38, 102.21, 106.70, 107.31, 113.75, 114.00, 116.42,
118.02, 122.21, 123.05, 123.70, 124.02, 124.69, 125.10,
126.59, 129.92, 130.78, 131.44, 136.60, 139.84, 140.36,
140.95, 142.17, 147.96, 158.06, 158.29, 160.90, 161.47,
163.72; HRMS (ES), Calcd for C36H39N4O5 (M11H):
607.2920; Found: M11H: 607.2913.
Bis-BOC-guanidine 19. Synthesised following a similar
procedure to that for 12 to give 19 as a white foam (83%).
1
IR (®lm) nmax 1762, 1720, 1642, 1596 cm21; H NMR
(300 MHz, CDCl3) dH, 0.93 (6H, d, Jˆ6.6 Hz), 1.51 (9H,
s), 1.53 (9H, s), 1.63 (2H, q, Jˆ6.6 Hz), 1.75±1.82 (1H, m),
2.26 (3H, s), 2.99±3.04 (2H, m), 3.91 (2H, t, Jˆ6.6 Hz),
4.75±4.80 (2H, m), 4.97 (2H, s), 5.11 (2H, s), 6.55 (1H, t,
Jˆ2.2 Hz), 6.60 (1H, m), 6.62±6.63 (1H, m), 6.71 (1H, d,
Jˆ9.5 Hz), 6.85±6.89 (2H, m), 6.96±6.99 (2H, m), 7.11±
7.18 (4H, m), 7.31 (1H, t, Jˆ8.0 Hz), 7.55 (1H, brs), 7.62
(1H, d, Jˆ9.5 Hz), 7.64±7.67 (1H, m), 10.35 (1H, s), 11.66
(1H, brs); 13C NMR (75 MHz, CDCl3) dC, 21.15, 22.60,
25.06, 28.19, 35.45, 37.93, 48.30, 66.68, 69.94, 72.41,
101.95, 106.76, 107.12, 115.02, 121.05, 121.43, 122.16,
122.22, 122.49, 122.84, 123.43, 123.85, 129.42, 129.99,
130.80, 137.09, 137.34, 137.78, 138.27, 139.74, 147.43,
149.21, 153.59, 153.80, 160.62, 161.10, 163.70, 163.82,
169.77; HRMS (ES), Calcd for C49H58N4O10 (M11H):
863.4231; Found: M11H: 863.4226.
2-(4-Acetoxyphenyl)ethanol 15. Synthesised following a
similar procedure to that for 3-acetoxybenzyl alcohol to
give 15 as a colourless oil (73%). CHN Calcd for
1
C10H12O3: C, 66.65; H, 6.71. Found: C, 66.61; H, 6.64; H
NMR (300 MHz, CDCl3) dH, 2.26 (3H, s), 2.34 (1H, brs),
2.78 (2H, t, Jˆ6.6 Hz), 3.74 (2H, t, Jˆ6.6 Hz), 6.97±7.01
(2H, m), 7.17±7.22 (2H, m); 13C NMR (75 MHz, CDCl3)
dC, 21.10, 38.55, 63.48, 121.72, 130.23, 136.68, 149.39,
170.14; LRMS 180 (M1, 6%), 138 (40%), 107 (100%).
2-(4-Acetoxyphenyl)ethyl bromide 16. Colourless oil
(78%). CHN Calcd for C10H11O2Br: C, 49.41; H, 4.56; Br,
32.87. Found: C, 49.46; H, 4.49; Br, 32.65; 1H NMR
(300 MHz, CDCl3) dH, 2.27 (3H, s), 3.14 (2H, t, Jˆ
7.6 Hz), 3.53 (2H, t, Jˆ7.6 Hz), 7.01±7.05 (2H, m), 7.18±
7.23 (2H, m); 13C NMR (75 MHz, CDCl3) dC, 21.13, 32.75,
38.78, 121.89, 129.86, 136.65, 149.82, 169.73; LRMS 244
(M1, 6%), 242 (M1, 6%), 202 (39%), 200 (42%), 107 (100%).
Deacetylation of bis-BOC-guanidine 19 to give 19a. The
acetate protecting group was removed from 19 following an
identical procedure to that for 12 to give 19a as a white foam
(84%). IR (®lm) nmax 3263, 1721, 1646, 1612, 1596,
1
1516 cm21; H NMR (300 MHz, CDCl3) dH, 0.93 (6H, d,
8-[30-(3-i-Pentyloxy)-50-(300-N-BOC-aminobenzyloxy)-
benzyloxy]-2-[1-(4000-acetoxyphenyl)ethyl]quinolinone
17. Synthesised following a similar procedure to that for 9 to
give 17 as a pale yellow foam (31%). IR (®lm) nmax 1760,
Jˆ6.6 Hz), 1.47 (9H, s), 1.54 (9H, s), 1.64 (2H, q,
Jˆ6.6 Hz), 1.74±1.85 (1H, m), 2.90±2.95 (2H, m), 3.94
(2H, t, Jˆ6.6 Hz), 4.73 (2H, s), 4.81±4.87 (2H, m), 5.12
(2H, s), 6.55±6.56 (1H, m), 6.59±6.61 (2H, m), 6.65±6.68
(2H, m), 6.73 (1H, d, Jˆ9.5 Hz), 6.81±6.84 (2H, m), 7.09±
7.11 (1H, m), 7.15±7.22 (3H, m), 7.29 (1H, t, Jˆ7.8 Hz),
7.44±7.47 (1H, m), 7.59±7.60 (1H, m), 7.62 (1H, d,
Jˆ9.5 Hz), 10.34 (1H, s), 11.71 (1H, brs); 13C NMR
(75 MHz, CDCl3) dC, 22.61, 25.09, 28.17, 35.10, 37.96,
48.36, 66.69, 69.67, 72.66, 80.20, 84.07, 102.27, 106.34,
107.70, 115.19, 115.64, 122.06, 122.17, 122.53, 122.72,
1
1724, 1651, 1594 cm21; H NMR (300 MHz, CDCl3) dH,
0.93 (6H, d, Jˆ6.6 Hz), 1.50 (9H, s), 1.63 (2H, q, Jˆ
6.6 Hz), 1.72±1.83 (1H, m), 2.28 (3H, s), 2.95±3.00 (2H,
m), 3.91 (2H, t, Jˆ6.6 Hz), 4.70±4.75 (2H, m), 4.93 (2H, s),
5.09 (2H, s), 6.55 (1H, t, Jˆ2.2 Hz), 6.63±6.61 (2H, m),
6.71 (1H, d, Jˆ9.5 Hz), 6.84±6.94 (5H, m), 7.00±7.03 (1H,
m), 7.11±7.26 (4H, m), 7.36±7.38 (2H, m), 7.61 (1H, d,

Z.-X. Guo et al. / Tetrahedron 56 (2000) 5169±5175
5175
122.97, 123.60, 124.45, 129.38, 129.78, 130.05, 130.75,
136.84, 138.00, 138.11, 139.88, 147.60, 153.57, 154.48,
155.48, 160.71, 160.92, 163.68, 163.91; HRMS (ES), Calcd
for C47H57N4O9 (M11H): 821.4125; Found: M11H:
821.4133.
57.38; H, 5.29; N, 8.47. Found: C, 57.54; H, 4.98; N, 8.09;
1
IR (®lm) nmax 3356, 3183, 1657, 1604 cm21; H NMR
(300 MHz, d6-acetone) dH, 0.93 (6H, d, Jˆ6.6 Hz), 1.62
(2H, q, Jˆ6.6 Hz), 1.75±1.85 (1H, m), 3.16 (4H, s), 3.99
(2H, t, Jˆ6.6 Hz), 5.13 (2H, s), 5.25 (2H, s), 6.54 (1H, t,
Jˆ2.2 Hz), 6.58 (1H, d, Jˆ9.6 Hz), 6.72 (1H, m), 6.83 (1H,
m), 7.12 (1H, t, Jˆ7.8 Hz), 7.20±7.27 (3H, m), 7.32±7.43
(3H, m), 7.88 (1H, d, Jˆ9.6 Hz), 7.98 (brs), 10.26 (1H, brs),
11.03 (1H, s); 13C NMR (75 MHz, d6-acetone) dC, 22.84,
25.75, 38.69, 67.08, 69.81, 71.32, 102.10, 107.19, 107.74,
113.26, 120.81, 121.13, 123.05, 124.58, 125.10, 126.45,
129.88, 130.73, 136.69, 139.80, 140.38, 141.58, 145.51,
158.07, 160.91, 161.42, 162.82; HRMS (CI), Calcd for
C29H32N4O4 (M11H): 501.2502; Found: M11H: 501.2492.
Dendroid II. Synthesised following a similar procedure to
that for dendroid I to give dendroid II as a white foam
(75%). CHN Calcd for C37H40N4O.5 1.1 TFA. 1.3 H2O: C,
61.18; H, 5.72; N, 7.28; F, 8.15. Found: C, 60.89; H, 5.50;
N, 6.98; F, 7.97 IR (®lm) nmax 3346, 1685, 1649,
1
1595 cm21; H NMR (300 MHz, acetone-d6) dH, 0.92 (6H,
d, Jˆ6.6 Hz), 1.63 (2H, q, Jˆ6.6 Hz), 1.73±1.87 (1H, m),
2.82±2.88 (2H, m), 3.10 (brs), 4.00 (2H, t, Jˆ6.6 Hz), 4.67±
4.73 (2H, m), 5.01 (2H, s), 5.26 (2H, s), 6.59±6.66 (4H, m),
6.74±6.82 (4H, m), 7.20 (1H, t, Jˆ8.0 Hz), 7.27±7.44 (6H,
m), 7.79 (1H, d, Jˆ9.6 Hz), 7.95 (brs), 11.08 (1H, s); 13C
NMR (75 MHz, acetone-d6) dC, 22.84, 25.77, 35.88, 38.65,
48.89, 67.17, 69.94, 72.81, 102.60, 107.89, 108.52, 115.92,
122.41, 123.07, 123.48, 123.97, 124.83, 125.19, 126.70,
130.42, 130.73, 130.76, 131.34, 136.60, 139.46 140.23,
140.48, 147.98, 156.58, 158.07, 161.20, 161.67, 163.56;
HRMS (ES), Calcd for C37H40N4O5 (M11H): 621.3077;
Found: M11H: 621.3073.
Acknowledgements
Support for this work from PDNRC is gratefully acknowl-
edged. We thank the EPSRC service centre at Swansea for
mass spectra, Mr A. Saunders (UEA) for elemental analyses
and Dr S. Menzler (PDNRC) for useful discussions.
References
8-[30-(3-i-Pentyloxy)-50-(300-aminobenzyloxy)benzyloxy]-
2-[1H]quinolinone 20. Synthesised following a similar
procedure to that for 10 to give 20 as a white foam (87%).
IR (®lm) nmax 3353, 1660, 1605 cm21; 1H NMR (300 MHz,
CDCl3) dH, 0.94 (6H, d, Jˆ6.6 Hz), 1.65 (2H, q, Jˆ6.6 Hz),
1.75±1.87 (1H, m), 3.60 (2H, brs), 3.95 (2H, t, Jˆ6.6 Hz),
4.94 (2H, s), 5.08 (2H, s), 6.52 (1H, t, Jˆ2.2 Hz), 6.56±6.61
(3H, m), 6.65 (1H, d, Jˆ9.6 Hz), 6.74±6.78 (2H, m), 6.96±
6.99 (1H, m), 7.07 (1H, t, Jˆ7.8 Hz), 7.11±7.15 (2H, m),
7.70 (1H, d, Jˆ9.6 Hz), 9.34 (1H, brs); 13C NMR (75 MHz,
CDCl3) dC, 22.63, 25.12, 38.02, 66.73, 70.38, 71.20, 101.90,
106.51, 106.87, 111.83, 114.15, 114.95, 117.63, 120.08,
120.37, 122.37, 122.83, 129.00, 129.74, 138.15, 138.26,
140.63, 144.81, 147.10, 160.70, 160.99, 162.28; HRMS
(CI), Calcd for C28H30N2O4 (M11H): 459.2284; Found:
M11H: 459.2273.
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Bis-BOC-guanidine 21. Synthesised following a similar
procedure to that for 12 to give 21 as a white foam (54%).
IR (®lm) nmax 1719, 1651, 1608 cm21; 1H NMR (300 MHz,
CDCl3) dH, 0.95 (6H, d, Jˆ6.6 Hz), 1.52 (18H, s), 1.66 (2H,
q, Jˆ6.6 Hz), 1.78±1.86 (1H, m), 3.97 (2H, t, Jˆ6.6 Hz),
5.04 (2H, s), 5.11 (2H, s), 6.53 (1H, t, Jˆ2.2 Hz), 6.58±6.61
(2H, m), 6.66 (1H, d, Jˆ9.6 Hz), 6.98±7.01 (1H, m), 7.08
(1H, t, Jˆ7.7 Hz), 7.13±7.18 (2H, m), 7.33 (1H, t,
Jˆ7.7 Hz), 7.58 (1H, brs), 6.66±6.69 (1H, m), 7.72 (1H,
d, Jˆ9.6 Hz), 9.30 (1H, s), 10.36 (1H, s), 11.66 (1H, brs);
13C NMR (75 MHz, CDCl3) dC, 22.59, 25.00, 28.12, 37.92,
66.54, 69.83, 71.03, 79.64, 83.75, 101.60, 106.29, 106.68,
111.52, 119.84, 120.11, 120.88, 121.94, 122.17, 122.57,
123.68, 128.66, 129.20, 137.10, 137.59, 137.86, 140.41,
144.51, 153.31, 153.53, 160.16, 160.68, 161.97, 163.45;
HRMS (ES), Calcd for C39H48N4O8 (M11H): 701.3550;
Found: M11H: 701.3557.
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Dendroid III. Synthesised following a similar procedure to
that for dendroid I to give dendroid III as a white foam
(76%). CHN Calcd for C29H32N4O4. 1.3 TFA. 0.7 H2O: C,
15. Schmidt, U.; Lieberknecht, A.; Griesser, H.; Talbiersky, J. J.
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